Certain 1-(2-tertiary aminoethoxy) guanidines and their preparation



United States Patent 0 3,200,111 CERTAIN I-(Z-TERTIARY AMINOETHOXY)GUANI- DINES AND THEIR PREPARATION Leo A. Paquette, Portage Township, Kalamazoo County, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Aug. 27, 1963, Ser. No. 304,974

6 Claims. (Cl. 260-239) This invention relates to novel compounds and to a process for their preparation and is particularly directed to novel 1-(2-aminoethoxy)guanidines and their preparation.

The novel 1-(2-aminoethoxy)guanidines are represented by the formula:

RRNomoHr-o-NH-ii-NH, (I) wherein RRN- is selected from the group consisting of diloweralkylamino and the heterocyclic moieties, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, hexahydroazepinyl, heptamethylenimino, octamethylenimino, morpholino, and thiomorpholino, each of said heterocyclic moieties having attached as substituents on carbon atoms thereof zero to 3 loweralkyls, inclusive. When RRN is diloweralkylarnino, the loweralkyls, R, can be the same or different. When RRN is a heterycyclic moiety with 2 or more alkyls, the alkyls can be the same or different. Examples of loweralkyls within the scope of diloweralkylamino are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and the isomeric forms thereof. Examples of heterocyclic moieties within the scope of RRNare aziridinyl, 2-methylaziridinyl, Z-ethylaziridinyl, 2-butylaziridinyl, 2,3-dimethylaziridinyl, 2,2-dimethylaziridinyl, azetidinyl, 2-methylazetidinyl, B-methylazetidinyl, 2-octylazetidinyl, 2,2-dimethylazetidinyl, 3,3-diethylazetidinyl, 2,4,4-trimethylazetidinyl, 2,3,4-trimethyl-azetidinyl, pyrrolidinyl, Z-methylpyrrolidinyl, 3-butylpyrrolidinyl, 2-isohexylpyrrolidinyl, 2,3-dimethylpyrrolidinyl, 2,2-dimethylpyrrolidinyl, 2,5-diethylpyrrolidinyl, 3-tertbutylpyrrolidinyl, 2,3,S-trimethylpyrrolidinyl, 3,4-dioctylpyrrolidinyl, piperidino, Z-methylpiperidino, 3-methylpiperidino, 4-methylpiperidino, 3-isopropylperidino, 4-tertbutylpiperidino, 2-methyl-S-ethylpiperidino, 3,5-dipentylpiperidino, 2,4,6-trimethylpiperidino, 2,6-dimethyl-4-octylpiperidino, 2,3,5-triethylpiperidino, hexahydroazepinyl, Z-ethylhexahydroazepinyl, 4-tert-butylhexahydroazepinyl, 3 heptylhexahydroazepinyl, 2,4 dimethylhexahydroazepinyl 3,3-dimethylhexahydroazepinyl, 2,4,6-tripropylhexahydroazepinyl, heptamethylenimino, Z-methylheptamethylenimino, S-butylheptamethylenimino, 2,4-diisopropylheptamethylenimino, 3,3 diethylhept-amethylenimino, 2,5,8-trimethylheptamethylenimino, octamethylenimino, 3-methyloctamethylenimino, 2,9-diethyloctamethylenimino, 4-isooctyloctamethylenimino, morpholino, 2 ethylmorpholino, Z-methyl-Sethylmorpholino, 3,3- dimethylmorpholino, 2,G-ditert-butylmorpholino, thiamorpholino, 3 methylthiamorpholino, 2,2 diethylthiamorpholino, 2,-dihexylthiamorpholino, and the like. In each of the above examples of heterocyclic moieties, the free valence, and hence the point of attachment to the oxygen atom in Formula I, is on the heterocyclic nitrogen atom.

The novel 1-(2-aminoethoxy)guanidines of Formula I exist either in the nonprotonated (free base) form or the protonated form depending upon the pH of the environment. They form stable protonates (acid addition salts) on neutralization with suitable acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, thiocyanic, fluosilicic, acetic, benzoic, salycylic, glycolic, succinic, nicotinic, tartaric, maleic, malic, lactic, methanesulfonic, and cyclohexanesulfamic acids, and the like. T ese a i addit on. saltsa e .H QfLilJJL PgrQQina-..

"ice

the freebases The corresponding-free bases are useful wherein RRN- is as given above. The reaction advantageously is effected in aqueous solution at reflux temperature for about 2 to about 20 hours. The resulting sulfate salt can be converted to the free base form by treatment with aqueous alkali hydrxide, e.g., soduim or potassium hydroxide, and the liberated free base can be converted to other acid addition salts by neutralization with acid. Acid addition salts of the sulfate or other mono salts can be formed in the same manner. Acid addition salts can also be formed by metathesis.

The thiocyanic acid addition salts of the 1-(2-aminoethoxy)guanidines of Formula I, when condensed with formaldehyde, form resinous materials useful as pickling inhibitors according to US. Patents 2,425,320 and 2,606,155. The compounds of Formula I also form fluosilicic acid addition salts which are useful as mothproofing agents according to US. Patents 1,915,334 and 2,075,359.

The Formula I compounds of this invention also form salts with penicillins. These salts have solubility characteristics which cause them to be useful in the isolation and purification of penicillins, particularly benzyl penicillin. Said salts can be formed either by neutralization of the free base form of a compound of Formula I with the free acid form of a penicillin, or by a metathetical exchange of the anion of an acid addition salt of a compound of Formula I, for example, the chloride ion of a hydrochloride, with the anionic form of a penicillin.

The novel compounds of Formula I in their protonated and nonprotonated forms exhibit anorexigenic, hypotensive, and anti-inflammatory activities in' test animals such as mice and rats and are useful as in arresting or alleviating hunger, hypertension, and inflammation in mammals, e.g., man and rodents, birds, e.g., poultry, and other animals.

The aminoethoxyamine starting compounds can be prepared by reacting an alkali metal salt of acetone oxime, e.g., sodium acetone oxime, with a chloroethylamine of the formula:

RRNCHzCHz-Cl (III) to form a compound of the formula:

CH3 (IV) RRNCH:CHr-0N=C and subjecting the oxime IV to acid hydrolysis to form starting compounds of Formula II, RRN- being as given above. For example, 2-diloweralkylaminoethoxyamines can be prepared by the'procedure of Examples 1 and 3 of US. Patent 3,060,177 and the Z-cyclicaminoethoxyamines by substituting theappropriate 2-cyclicaminoethyl chloride for the 2-diloweralkylaminoethyl chlorides used in these examples. The novel compounds of the invention can also be produced by substituting 2- methyl-2-thiopseudoure and water for the pyridine aldehydes and alcohol, respectively, of Examples 1, 3, 22, and 24 of US. Patent 3,060,177.

The invention may be more fully understood by the following examples which embody the best manner known for carrying out the invention.

Example I .--1- [2-(1 -hexahydroazepinyl) ethoxy]guanidine hydrogen sulfate A solution of 15.8 g. (0.10 mole) of 1-(2-aminooxyethyl)hexamethylenimine and 13.9 g. (0.10 mole) of 2- methyl-Z-thiopseudourea sulfate in 65 ml. of water was refluxed for 4 hours. The solution was concentrated to one-half of its original volume and treated with an equal volume of ethanol. After cooling, the white crystals were removed by filtration and dried to give 12.8 g. (86.0% of 1-[2-(1-hexahydroazepinyl)ethoxy]guanidine hydrogen sulfate, MP. 215 C. (with prior sintering at 180 C.). Three recrystallizations of this material from aqueous ethanol gave white needles, M.P. 255256 C.

Analysis.-Calcd. for CgH22N405S C, 36.23; H, 7.43; N, 18.78. Found: C, 36.26; H, 7.59; N, 18.56.

Example 2.1-[2-(1-pyrr0lidinyl) ethxy]guanidine hydrogen sulfate A solution of 13.0 g. (0.10 mole) of I-(Z-aminooxyethyl)pyrrolidine and 13.9 g. (0.10 mole) of 2-methyl-2- thiopseudourea sulfate in 65 ml. of water was refluxed for 4 hours. The solution was concentrated to one-half of its original volume and treated with an equal volume of ethanol. After cooling, the white crystals were removed by filtration and dried to give 10.5 g. (78.2%) of 1- [2-( 1-pyrrolidinyl)ethoxy]guanidine hydrogen sulfate, M.P. 240-243 C. (dec.). Three recrystallizations of this material from aqueous ethanol gave clusters of white needles, M.P. 246-247 C. (dec.).

Analysts-Calm. for C7H1gN O5SZ C, 31.10; H, 6.71; N, 20.73. Found: C, 31.28; H, 6.50; N, 20.52.

By substituting the l-(2-aminooxyethyl)hexamethylenimine and 1-(Z-aminooxyethyl)pyrrolidine of Examples 1 and 2 by N-(Z-aminooxyethyl)dimethylamine,

N- Z-aminooxyethyl diethylamine, N-(Z-aminooxyethyl)dipropylamine, N-(Z-aminooxyethyl)dii-sopropylamine,

N- Z-aminooxyethyl N-methylisopropyl amine, N-(2-aminooxyethyl)dibutylamine, N-(Z-aminooxyethyl)di-sec-butylamine, N-(Z-aminboxyethyl)diisobutylamine,

N- Z-aminooxyethyl di-tert-butylamine, N-(2-aminooxyethyl)-N-methylbutylamine,

N- 2-aruinooxyethyl -N-ethyl-sec-buty1amine,

N- (2-aminooxyethyl dipentylamine, N-(Z-aminooxyethyl)diisopentylamine, N-(Z-aminooxyethyl)-N-methylpentylarnine,

N- (Z-aminooxyeth yl -N-ethyl-2-methylbutylamine, N-(2-aminooxyethyl)dihexylamiue,

N- (2-aminooxyethyl diisohexyl amine,

N- Z-aminooxyethyl -N-methylhexylamine,

N-(Z-aminooxyethyl)-N-ethyl-2,3-dimethylbutylamine, N-(Z-aminooxyethyl)-N-ethyl-propylarnine, l-(2-arninooxyethyl)aziridine, 1-(Z-aminooxyethyl)-2-methy1aziridine,

l- (Z-aminooxyethyl -2,3-dirnethylaziridine, 1-(2-aminooxyethyl)-2,2-dimethylazi1idine, 1- 2- aminooxyethyl azetidine,

1- (Z-aminooxyethyl -2-methyl azetidine,

l- (Z-aminooxyethyl -3-methylazetidine, 1-(Z-aminooxyethyl)-2-octylazetidine,

l- (2-aminooxyethyl -2,2-dimethylazetidine, 1-(2-aminooxyethyl)-3,3-dimethylazetidine, I-(Z-aminooxyethyl)-2,4,4-trimethylazetidine, l-(Z-aminooxyethyl)pyrrolidine, l-(Z-aminooxyethyl)-2-rnethylpyrrolidine, 1-(2-aminooxyethyl)-3-butylpyrrolidine, 1-(Z-aminooxyethyl)-2-isohexylpyrrolidine, 1-(2-aminooxyethyl)-2,3-dimethylpyrrolidine, 1-(2-aminooxyethyl)-2,2,4-trimethylpyrrolidine,

' l- Z-aminooxyethyl) -2,2-dime thylpyrrolidine,

1-(Z-aminooxyethyl)-2,5-diethy1pyrrolidine, 1-(Z-aminooxyethyl)-3-tert-butylpyrrolidine, 1-(2-aminooxyethyl)-3,4-dioctylpyrrolidine, 1-(2-aminooxyethyl)piperidine,

1-( Z-aminooxyethyl)-2-methylpiperidine, l-(Z-arninooxyethyl)3-methylpiperidine, 1-(2-aminooxyethyl)-4-methylpiperidine, l-(2-amino0xyethyl -3-isopropylperidine,

1- (2- aminooxyethyl 4-tert-butylpiperidine, 1-(Z-aminooxyethyl)-2,4,6-trimethylpiperidine, 1-(2-aminooxyethyl)-2-methyl-5-ethylpiperidine, l-(2-aminooxyethyl)-3,S-dipentylpiperidine, l-(Z-aminooxyethyl)-2,G-dimethyl-4-octylpiperidine, 1-(Z-aminooxyethyl)hexahydroazepine,

l-( Z-aminooxyethyl -2-ethylhexahydroazepine,

1- (Z-aminooxyethyl -4-tert-butylhexahydroazepine, 1-(2-aminooxyethyl)-3,3-dimethylhexahydroazepine, 1-(Z-aminooxyethyl)-2,4,6-tripropylhexahydroazepine, 1-(Z-aminooxyethyl)heptamethylenimine, I-(Z-aminooxyethyl)-2-ethylheptamethylenimine, l-(Z-aminooxyethyl)-2,4-diisopropylheptamethylenimine, 1-( Z-aminooxyethyl) -3 ,3-dimethylheptamethylenimine, 1- Z-aminooxyethyl) octamethylenimine, l-(2-aminooxyethyl)-3 -methyloct-amethylenimine, l-(Z-aminooxyethyl)-4-isoocty1octamethylenimine, 1-(2-aminooxyethy1)morpholine, l-(2-arninooxyethyl)-2,2-diethylmorpholine,

1- 2-aminooxyethyl) -2-methy1-5 -ethylm orpholine, 1-(2-aminooxyethyl)-3,3-dimethylmorpholine, l-(2-aminooxyethyl)thiamorpholine, 1-(2-aminooxyethy1)-3-methylthiamorpholine, and 1-(Z-aminooxyethyl)-2,2-dipentylthiamorpholine, there are obtained 1-[2-(dimethylarnino)ethoxylguanidine hydrogen sulfate,

1-[2-(diethylamino)-ethoxy] guanidine hydrogen sulfate,

l-[2-(dipropylamino)-ethoxy] guanidine hydrogen sulfate, 1-[2-(diisopropylamino)-ethoxy)guanidine hydrogen sulfate, 1-[2-(N-methylisopropylamino)ethoxy]guanidine hydro gen sulfate, 1-[2-(dibutylamino)-ethoxy]guanidine hydrogen sulfate, l-[2-(di-sec-butylamino)-ethoxy]guanidine hydrogen sulfate, 1-[Z-(diisobutylamino)-ethoxy]guanidine hydrogen sulfate, l-[Z-(di-tert-butylamino)-ethoxy]guanidine hydrogen sulfate, l-[2-(N-methylbutylamino)ethoxy] guanidine hydrogen sulfate, 1-[2-(N-ethyl-sec-butylamino)ethoxy]guanidine hydrogen sulfate, 1-[2-dipentylamino)ethoxy] guanidine hydrogen sulfate, l-[Z-(diisopentylamino)ethoxyjguanidine hydrogen sulf-ate, 1-[2-( N-methylpentylamino ethoxy] guanidine hydrogen sulfate, 1 -[2-(N-ethyl-2-methylbutylamino)ethoxy]guanidine hydrogen sulfate, 1-[2-(dihexy1amino)ethoxy] guanidine hydrogen sulfate, l- [2-(diisohexylamino) ethoxy] guanidine hydrogen sulfate, 1- [2- (N-methylhexylamino) ethoxy1guam'dine hydrogen sulfate, 1-[2-(N-ethyl-2,3-dimethylbutyl-amino)ethoxy]guanidine hydrogen sulfate, l-[Z-(N-ethylpropylamino)ethoxy] guanidine hydrogen sulfate, 1-[2-(l-aziridinyl)ethoxy1guanidine hydrogen sulfate, 1-[2-(2-methyl-l-aziridinyl)ethoxy]guanidine hydrogen sulfate, 1-[2-(2,3-dirnethyl-l-aziridinyl) ethoxy] guanidine hydrogen sulfate, 1-[2-(2,2-dimethyl-l-aziridinyl)ethoxy]gu-anidine hydrogen sulfate, 1-[2-(l-azetidinyl)ethoxy] guanidine hydrogen sulfate, 1-[2-(2-methyl-l-azetidinyl) ethoxy] guanidine hydrogen sulfate, 1-[2-(3-methyl-l-azetidinyl)ethoxy]guanidine hydrogen sulfate,

1-[2-(2-octyl-l-azetidinyl)ethoxy]guanidine hydrogen sulfate,

1-[2-(2,2-dimethyl-1-azetidinyl)ethoxy] guanidine hydrogen sulfate,

1- [2- 3 ,3-diruethyl-1-azetidinyl)ethoxy]guanidine hydrogen sulfate,

1- [2-(2,4,4-trimethyl-l-azetidinyl)ethoxy] guanidine hydrogen sulfate,

1-[2-( l-pyrrolidinyl)ethoxy]guanidine hydrogen sulfate,

1- [2-(Z-methyl-l-pyrrolidinyl) ethoxy] guanidine hydrogen sulfate,

1-[2-(3-butyl-1-pyrrolidinyl)ethoxy1guanidine hydrogen sulfate,

1-[2-(2-isohexyl-l-pyrrolidinyDethoxy] guanidine hydrogen sulfate,

1-[2-(2,3-dimethyl-l-pyrrolidinyl)ethoxy] guanidine hydrogen sulfate,

1- [2-( 2,2,4-trimethyll-pyrrolidinyl) ethoxy1guanidine hydrogen sulfate,

1-[2-(2,2-dimethyl-l-pyrrolidinyl)ethoxy]-guanidine hydrogen sulfate,

1-[2-(2,5-diethyl-l-pyrrolidinyDethoxy] guanidine hydrogen sulfate,

1-[2-(3-tert-hutyl-1-pyrrolidinyl)ethoxy]guanidine hydrogen sulfate,

1-[2-(3,4-dioctyl-l-pyrrolidinyDethoxy] guanidine hydrogen sulfate,

1-[2-(piperidino)ethoxy] guanidine hydrogen sulfate,

1-[2-(2-methylpiperidino)ethoxy]guanidine hydrogen sulfate,

I-[Z-(S-methylpiperidino)ethoxy1guanidine hydrogen sulfate,

l- [2- (4-methylpiperidino) ethoxy] guanidine hydrogen sulfate,

1-[2-(3-isopropylpiperidino) ethoxy] guanidine hydrogen sulfate,

1- 2-(4-tert-butylpiperidino) ethoxy] guanidine hydrogen sulfate,

1-[2-(2,4,6-trimethylpiperidino)ethoxy] guanidine hydrogen sulfate,

1- [2-(2-methyl-5-ethylpiperidino) ethoxy] guanidine hydrogen sulfate,

1-[2-(3,S-dipentylpiperidino)ethoxy] guanidine hydrogen sulfate,

1- [2- (2,6-dimethyl-4-oetylpiperidino) ethoxy] guanidine hydrogen sulfate,

1- [2-( l-hexahydroazepinyl) ethoxy] guanidine hydrogen sulfate,

1-[-(2-ethyl-l hexahydroazepinyl)ethoxy] guanidine hydro gen sulfate,

1- [2- (4-tert-butyl- 1hexahydroazepinyl) ethoxy] guanidine hydrogen sulfate,

1-[2-(3,B-dimethyl-l-hexahydroazepinyl)ethoxy] guanidine hydrogen sulfate,

1- 2- (2,4,6-tripropyll-hexahydroazepinyl) ethoxy] gu-anidine hydrogen sulfate,

6 1- [2- (heptamethylenimino) ethoxy] guanidine hydrogen sulfate, 1-[2-(Z-ethylheptamethylenim-ino)ethoxy] guanidine hydrogen sulfate, 1-[2-(2,4-diisopropylheptamethylenimino)ethoxy]guanidine hydrogen sulfate, 1-[2-(3,3-dimethylheptamethylenimino)ethoxy]guanidine hydrogen sulfate, 1-[2-(octamethylenimino)ethoxy]guanidine hydrogen sulfate, l-[2-(3-methyloctamethylenimino)ethoxy]guanidine hydrogen sulfate, 1-[2-(4-isooctyloctamethylenimino)ethoxy] guanidine hydrogen sulfate, 1- [2-( morpholino ethoxy] guanidine hydrogen sulfate, 1- [2-(2,2-diethylmorpholino) ethoxy] guanidine hydrogen sulfate, 1-[2-(Z-methyl-5ethylmorpholino)ethoxy] guanidine hydrogen sulfate, 1- [2-( 3 ,3-dimethylmor'pholino) ethoxy] guanidine hydrogen sulfate, 1-[2-(thiamorpholino)ethoxy] guanidinehydrogen sulfate, 1-[2-(B-methylthiamorpholino)ethoxy] guanidine hydrogen sulfate, and 1- [2-(2,2-dipentylthiam0rpholino)ethoxy1guanidine hydrogen sulfate, respectively. I claim: 1. A compound selected from the group consisting of the free base and acid addition salt forms of a compound of the formula:

wherein RRN- is selected from the group consisting of diloweralkylamino and the heterocyclic moieties, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, hexahydroazepinyl, heptamethylenimino, octamethylenimino, morpholino, and thiamorpholino, each of said heterocyelic moieties having attached as substituents on carbon atoms thereof zero to 3 loweralkyls, inclusive.

2. 1- [2-( l-hexahydroazepinyl)ethoxy] guanidine hydrogen sulfate.

3. l- [2-( l-hexahydroazepinyl) ethoxy] guanidine. f 4. 1-[2-(l-pyrrolidinyDethoxy]guanidine hydrogen sulate.

5. 1- [2-( l-pyrrolidinyl) ethoxy] guanidine.

6. The method of making compounds of claim 1 which comprises reacting 2-methyl-2-thiopseud0urea with a compound of the formula:

RRNCH CH -O--NH wherein RRN is as given in claim 1.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE FREE BASE AND ACID ADDITION SALT FORMS OF A COMPOUND OF THE FORMULA: (R)2-N-CH2-CH2-O-NH-C(=NH)-NH2 WHEREIN RRN-IS SELECTED FROM THE GROUP CONSISTING OF DILOWERALKYLAMINO AND THE HETEROCYCLIC MOIETIES, AZIRIDINYL, AZETIDINYL, PYROLIDINYL, PIPERIDINO, HEXAHYDROAZEPINYL, HEPTAMETHYLENIMINO, OCTAMETHYLEUIMINO, MORPHOLINO, AND THIAMORPHOLINO, EACH OF SAID HETEROCYCLIC MOIETIES HAVING ATTACHED AS SUBSTITUENTS ON CARBON ATOMS THEREOF ZERO TO 3 LOWERALKYLS, INCLUSIVE.
 6. THE METHOD OF MARKING COMPOUNDS OF CLAIM 1 WHICH COMPRISES REACTING 2-METHYL-2-THIOPSEUDOUREA WITH A COMPOUND OF THE FORMULA: 